An active ingredient hardly (or sparingly) soluble in water (e.g., a fibrate-series active ingredient) remarkably deteriorates bioavailability due to a low solubility (or dissolution rate) or dispersibility thereof. In order to improve the solubility of the active ingredient, various formulations have been examined, for example, pulverization of the active ingredient, a solid dispersion containing a carrier solubilizing an active ingredient and the active ingredient dispersed in the carrier, and a solid dispersion containing the active ingredient supported on or to a powdery porous carrier by impregnation.
For example, European Patent Application Publication No. EP330532 (Patent Document 1) discloses that the bioavailability of fenofibrate is improved by co-pulverizing a surfactant (particularly sodium lauryl sulfate) and fenofibrate. International Publication No. WO98/31361 pamphlet (Patent Document 2) discloses adding a hydrophilic polymer containing finely powdered fenofibrate and a surfactant, each suspended therein, to an inactive carrier for improving the bioavailability of fenofibrate. However, these preparations still have insufficient drug solubility (or dissolution rate) or dispersibility and unsatisfactory bioavailability. Moreover, the handleability in the production process is deteriorated with making the particle size of the active ingredient fine.
Japanese Patent Application laid-Open No. 2003-500439 (JP-2003-500439A, Patent Document 3) discloses a composition which is a eutectic mixture of a lipid-regulating agent such as a fibrate and a statin and an excipient such as a polyethylene glycol. Japanese Patent Application laid-Open No. 2007-161588 (JP-2007-161588A, Patent Document 4) discloses a solid dispersion prepared by melt-mixing fenofibrate and a polyethylene glycol and solidifying the mixture, and the proportion of the fenofibrate relative to the solid dispersion is not less than 50% by mass. However, in these solid dispersions, the species of a usable and meltable carrier component is strictly limited depending on the species of the pharmacologically active ingredient. Further, since the pharmacologically active ingredient and the carrier component are melt-mixed, these techniques can apply only to thermally stable ones.
Regarding a solid dispersion utilizing a porous carrier, for example, Chemical & Pharmaceutical Bulletin (Japan), 35(9), 1987, p. 3800-3806 (Non-Patent Document 1) discloses that the solubility of a hardly soluble drug is improved by using a colloidal silica, which is one of porous powders, as a carrier and spray-drying the drug in a water system. Proceedings of the Annual Meeting of the Pharmaceutical Society of Japan, 121, 1999, p. 103 (Non-Patent Document 2) discloses that a colloidal silica carrier is added to indomethacin or tolbutamide to change the crystallinity of the principal ingredient, thereby improving the solubility. In Japanese Patent Application laid-Open No. 2004-10575 (JP-2004-10575A, Patent Document 5), the solubility of itraconazole is improved by mixing an inorganic porous substance (such as calcium silicate or light anhydrous silic acid) to itraconazole. In Japanese Patent Application laid-Open No. 2004-238348 (JP-2004-238348A, Patent Document 6), the bioavailability of itraconazole is improved by adsorbing an itraconazole solution to or on a core material comprising silic acid or a salt thereof and/or coating a core material comprising silic acid or a salt thereof with an itraconazole solution. Japanese Patent Application laid-Open No. 2006-506388 (JP-2006-506388A, Patent Document 7) discloses a pharmaceutical composition and cosmetic composition containing a hydrophobic and highly dispersible silicon dioxide having a tamping density of 70 to 400 g/L. This document also refers to a BET specific surface area of silicon dioxide of 50 to 400 m2/g. Japanese Patent Application laid-Open No. 2006-248922 (JP-2006-248922A, Patent Document 8) discloses a tablet obtained by compressing a mixture of a composite particle and other components, the composite particle being obtained by spray-drying a silica and a drug such as indomethacin or acetaminophen.
However, due to the bulkiness of a porous carrier such as silic anhydride, a size of a solid preparation is still large even if the solid dispersion is compressed. In particular, since the compression molding causes a strong bonding of the porous carrier such as silic anhydride, the dispersibility or disintegratability of the solid preparation is deteriorated, and therefore, the solubility (or dissolution rate) of the active ingredient is rather reduced.
International Publication No. WO 2004/096280 pamphlet (Patent Document 9) discloses a drug-containing composition obtainable by treating a composition containing a drug very hardly soluble in water and a porous substance with a supercritical liquid or subcritical liquid of carbon dioxide. This document exemplifies “SYLYSIA” (manufactured by Fuji Silysia Chemical Ltd.) and a fine-spherical porous silica “SUNSPHERE H-51” (manufactured by Asahi Glass Co., Ltd.) as silic acid or a salt thereof. The document mentions that the dissolution rate of the drug from the composition is improved. However, in order to improve the dissolution rate of the drug, it is essential to charge the drug and the porous substance in a pressure tight container, fill the container with carbon dioxide, and hot-pressurize the container for treating the drug and the porous substance with a supercritical liquid or subcritical liquid of carbon dioxide. Therefore, the process is industrially disadvantageous due to the complicated production steps. Further, when the composition is compressed for molding, the dispersibility or disintegratability of the resulting preparation is deteriorated, and the dissolution rate of the drug is reduced in some cases.
International Publication No. WO 2005/034920 pamphlet (Patent Document 10) discloses a solid oral dosage form comprising a fibrate dissolved in a hydrophobic, hydrophilic or water-miscible vehicle (a vehicle such as a polyethylene glycol) and a solid dosage form further comprising an excipient, and refers to Aeroperl (trademark) 300 (Degussa) as a carrier or excipient (oil-sorption material). This document discloses a method of manufacturing the solid oral dosage form comprising the steps of: bringing the vehicle in liquid form, maintaining the liquid vehicle at a temperature below the melting point of the fibrate, dissolving the desired amount of fibrate in the vehicle, spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, mechanically working the resulting composition to obtain particles, and subjecting the particulate material to conventional methods for preparing solid dosage forms. However, this method requires to prepare a solid dispersion by heating and dissolving the fibrate in the vehicle and to spray the molten solid dispersion on the carrier. In the spraying step, a special spray apparatus is needed, and the operation is complicated. Moreover, a relatively large amount of the vehicle, compared with the fibrate, is required for preparing the solid dispersion. In addition, since the molten solid dispersion is sprayed for deposit on a solid carrier having a temperature below the melting point of the vehicle, the active ingredient is localized on the surface of the carrier and the solubility (or dissolution rate) of the fibrate from the solid dosage form depends on the molten solid dispersion containing the fibrate and the vehicle, whereby the solubility (or dissolution rate) of the fibrate cannot be improved greatly. Therefore, it is difficult to make a preparation compact or small as well as improve the bioavailability of the fibrate drastically even in a low fibrate content of the preparation.
[Patent Document 1] EP330532 (Claims)
[Patent Document 2] International Publication No. WO98/31361 pamphlet (Claims)
[Patent Document 3] JP-2003-500439A (Claims)
[Patent Document 4] JP-2007-161588A (Claims)
[Patent Document 5] JP-2004-10575A (Claims)
[Patent Document 6] JP-2004-238348A (Claims)
[Patent Document 7] JP-2006-506388A (Claims)
[Patent Document 8] JP-2006-248922A (Claims)
[Patent Document 9] International Publication No. WO 2004/096280 pamphlet (Claims)
[Patent Document 10] International Publication No. WO 2005/034920 pamphlet (Claims)
[Non-Patent Document 1] “Chemical & Pharmaceutical Bulletin” (Japan), 35(9), 1987, p. 3800-3806
[Non-Patent Document 2] “Proceedings of the Annual Meeting of the Pharmaceutical Society of Japan”, 121, 1999, p. 103